British patent specification No. 1,306,517 discloses a process for converting chloropyridines to fluoropyridines by reaction with alkali metal fluorides in polar, aprotic solvents at temperatures of from 160.degree. to 250.degree. C. The solvent may or may not be mixed with water and the reaction is carried out in the presence of an acid, base or organic hydroxy compound as an "initiator". The preferred solvent is sulfolane (tetramethylene sulfone) and the preferred initiator is ethylene glycol.
In the sole example in the patent of 2,6-difluoropyridine preparation, a 62% conversion of 2,6-dichloropyridine to the difluoro derivative is reported as having been obtained by refluxing a mixture of about 2 moles of the dichloropyridine and about 8 moles of anhydrous KF in sulfolane (containing 1.2 wt. percent of ethylene glycol) for 2 hours at 225-235.degree. C.
Reaction temperatures as high as 225.degree. are not particularly attractive for 2,6-difluoropyridine production. The boiling point of the latter compound is only about 125.degree. at sea level and it is therefore necessary either to operate under a pressure at least equal to the (quite substantial) autogenous pressure of the reaction mixture or to allow the difluoro compound to distil out of the reaction mixture as formed and to provide for reflux return to avoid losses of the chloro/fluoro intermediate, which is also quite volatile. However, substantially lower reaction rates can be anticipated at lower temperatures. In fact, a reaction period of 25-30 hours is required to attain an 80% yield of the difluoropyridine at 150.degree., in DMSO, and much longer periods are required in other solvents, including sulfolane, at this temperature.
The use of DMSO as the reaction medium at higher temperatures is contraindicated by two considerations: (1) the solubility of KF in this solvent goes down, rather than up, as the temperature increases (see Table 1); and (2) DMSO is known (Traynelis et al., J. Org. Chem., 29, 221 (1964)) to slowly decompose at reflux temperature (.about.189.degree. C.) and (according to Finger and Starr, J.A.C.S., 81, 2674 (1959)) to react with halogen compounds. Substantial alteration of DMSO would then be expected at elevated temperatures in the presence of such inherently reactive compounds as 2,6-difluoro- or 2-chloro-6-fluoropyridine.
On the other hand, if the reaction period could be sufficiently shortened by use of an appropriate catalyst, an unacceptable degree of solvent decomposition might not result. According to the British patent specification No. 1,306,517, ethylene glycol is the "initiator" of choice. Therefore, despite the fact that ethylene glycol is known (Traynelis et al., loc. cit.) to promote alteration of DMSO, an attempt was made to employ the glycol as a catalyst for the reaction of 2,6-dichloropyridine with KF in DMSO at 186.degree. C. 74.35 and 13.3% yields, respectively, of the difluoro and chloro/fluoro products were attained in a reaction period of 5.5 hours. However, a total of about 11% of the dichloropyridine was found to have been converted to undesired, solvent-derived by-products. Accordingly, the use of such catalysts as ethylene glycol appears to be ruled out.
It is known that replacement of chloro substituents on aromatic rings by fluorine can be achieved at less elevated temperatures if the ring is also substituted with an activating group. Thus, Finger and Kruse reported (J.A.C.S., 78, 6034 (1956)) that a 47% yield of a monofluoro derivative was obtained by reacting 2,4-dichloronitrobenzene with excess KF in DMSO (dimethyl sulfoxide) at 180.degree.for 6 hours; they attributed this result to activation by the nitro group. Similarly, U.S. Pat. No. 3,629,424 discloses (Example 5) that 30 grams (a 34.7% yield) of 3,5-dichloro-2,6-difluoro-4-cyanopyridine was obtained by reacting 100 grams of tetrachloro-4-cyanopyridine in DMSO at 40-50.degree. for 5 hours. However, no way of introducing a subsequently removable activating group in 2,6-dichloropyridine is evident.
An alternative possibility, which does not appear to have been considered, is that the materials ordinarily employed in the reaction may contain one or more impurities which act as "negative catalysts" and/or are conducive to DMSO alteration. For example, Traynelis et al (loc. cit.) reported that the decomposition of DMSO is accelerated by acids.
As ordinarily supplied, DMSO does not contain any detectable amounts of acids and 2,6-dichloropyridine is thermally stable and is commonly employed as a distilled, acid-free, starting material. Thus, if the exchange reaction is being effected by an acidic material, the latter must be introduced as an impurity, in the KF used. However, the highest acid (HF) content present, according to suppliers specifications, in any of the several grades of KF available is only 0.02%. Thus, acidic impurities in the KF would not appear to constitute an obvious source of difficulty.
Nevertheless, it has in fact been discovered that even reagent grade KF may contain sufficient amounts of HF to have a serious, adverse effect when the KF/alpha-chloropyridine reaction is carried out in DMSO at temperatures substantially above 150.degree..